Although Down Syndrome (DS is the most common cause of mental disability in children and adults, the neurobiological basis of DS is poorly understood. Affecting 1 in every 700 live births, DS results from an extra copy of the 243 known genes on chromosome 21 (Hsa21), among the most important are those affecting the central nervous system (CMS). The increased dosage of genes of Hsa21 manifests as characteristic and specific defects in learning, memory, and language and movement, which correlate with developmental and functional abnormalities in the cortex, hippocampus and cerebellum. Furthermore, histological studies and magnetic resonance imaging of DS brains have documented smaller overall brain volumes, with disproportionally smaller cerebellum. Unraveling which of the genes on Hsa21 affect neurological development and function is crucial to our understanding of how mental impairment arises in DS individuals and ultimately provide insights for developing strategies to rectify or prevent such problems. One of the 243 genes on chromosome 21, DSCAM (Down Syndrome Cell-Adhesion Molecule) has emerged as a promising candidate for the mental retardation phenotype seen in DS individuals. DSCAM is one of the few genes on chromosome 21 that is highly and exclusively expressed in the CMS, such as the cortex, hippocampus, and cerebellum (all areas affected in DS). It is also interesting to note that DSCAM mRNA and protein levels have also been found to be elevated in cerebral homogenates and autopsied brains of individuals with DS. The specific aims of this proposal are 1. to characterize the morphological defects of cerebella isolated from Purkinje-cell specific DSCAM knockouts and 2. to investigate the role of heterophilic versus homophilic signaling in the development of Purkinje cells. The first aim will be examined by means of MRI, and morphological analysis via histology and immunohistochemistry, which will give insight to the biological function and significance of DSCAM. The second aim utilized well-established mixed cerebellar cultures from wild-type and DSCAM knockouts to examine how.heterophilic and/or homophilic signaling via DSCAM is involved in neurodevelopment, specifically of Purkinje cells. Here we explore how one of the overexpressed genes in DS contributes to the proper development and maturation of the brain and ultimately gain insight as to how its overexpression can cause the mental retardation so prevalently seen in DS. This study will lay a foundation for the development of therapeutic and preventative strategies in dealing with DS and other developmental disorders.